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J. Biol. Chem., Vol. 280, Issue 17, 16665-16675, April 29, 2005

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Identification of Protein Kinase A Catalytic Subunit as a Novel Binding Partner of p73 and Regulation of p73 Function^*

Takayuki Hanamoto, Toshinori Ozaki, Kazushige Furuya, Mitsuchika Hosoda, Syunji Hayashi, Mitsuru Nakanishi, Hideki Yamamoto, Hironobu Kikuchi, Satoru Todo, and Akira Nakagawara¶

From the Division of Biochemistry, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan and the Department of General Surgery, Hokkaido University School of Medicine, Kita-ku, Sapporo 060-8638, Japan

Post-translational modifications play a crucial role in regulation of the protein stability and pro-apoptotic function of p53 as well as its close relative p73. Using a yeast two-hybrid screening based on the Sos recruitment system, we identified protein kinase A catalytic subunit (PKA-C) as a novel binding partner of p73. Co-immunoprecipitation and glutathione S-transferase pull-down assays revealed that p73 associated with PKA-C in mammalian cells and that their interaction was mediated by both the N- and C-terminal regions of p73. In contrast, p53 failed to bind to PKA-C. In vitro phosphorylation assay demonstrated that glutathione S-transferase-p73-(1–130), which has one putative PKA phosphorylation site, was phosphorylated by PKA. Enforced expression of PKA-C resulted in significant inhibition of the transactivation function and pro-apoptotic activity of p73, whereas a kinase-deficient mutant of PKA-C had no detectable effect. Consistent with this notion, treatment with H-89 (an ATP analog that functions as a PKA inhibitor) reversed the dibutyryl cAMP-mediated inhibition of p73. Of particular interest, PKA-C facilitated the intramolecular interaction of p73, thereby masking the N-terminal transactivation domain with the C-terminal inhibitory domain. Thus, our findings indicate a PKA-C-mediated inhibitory mechanism of p73 function.

Received for publication, December 20, 2004 , and in revised form, January 31, 2005.

^* This work was supported in part by a grant-in-aid from the Ministry of Health, Labor, and Welfare for Third Term Comprehensive Control Research for Cancer; a grant-in-aid for scientific research on priority areas from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; and a grant-in-aid for scientific research from the Japan Society for the Promotion of Science. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Div. of Biochemistry, Chiba Cancer Center Research Inst., 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan. Tel.: 81-43-264-5431; Fax: 81-43-265-4459; E-mail: akiranak{at}chiba-cc.jp.

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